(a) Field of the Invention
This invention relates to novel compounds, Formula I, that permit the unexpectedly efficient and convenient resolution of racemic 4-demethoxydaunomycinone, the anthracycline aglycone of the anti cancer drug 4-demethoxydaunorubicin. This compound is disclosed in U.S. Pat. No. 4,161,480.
Daunorubicin and doxorubicin are effective antineoplastic drugs, although cumulative cardiac toxicity limits the total quantity of these drugs that may be administered during a course of treatment. 4-Demethoxydaunorubicin is also an effective antineoplastic drug, reportedly more active in mice than daunorubicin against sarcoma 180 and against L1210 and Gross leukemias. F. Arcamone et al. Synthesis and Antitumor Activity of 4-Demethoxydaunorubicin, 4-Demethoxy-7,9-diepidaunorubicin, and Their .beta. Anomers. Cancer Treat. Rep., 60, 829 (1976).
Although racemic 4-demethoxydaunorubicin may be prepared by several methods, not all isomers are equally active and some isomers are negligibly active. Since the glycoside moiety of daunosamine is difficult to prepare and thus expensive, a method of resolving the aglycone 4-demethoxydaunomycinone before coupling with daunosamine is desirable. The compounds of this invention provide a convenient means of completely resolving racemic 4-demethoxydaunomycinone. For example, reaction of racemic 4-demethoxydaunomycinone with readily available 1-menthoxyacetyl chloride, followed by separation of diastereomers, affords the isomer of Formula II used ultimately to prepare the more active and preferred isomer of 4-demethoxydaunorubicin. Moreover, isomer II can be prepared without contamination by the undesired isomer, Formula III. ##STR1##
(b) Prior Art
Several methods have been described for the preparation of racemic 4-demethoxydaunomycinone, for example, C. M. Wong et al. Synthetic Studies of Hydronaphthacenic Antibiotics. I. The Synthesis of 4-Demethoxy-7-O-methyl Daunomycinone. Can. J. Chem., 49, 2712 (1971); U.S. Pat. No. 4,161,480.
Various resolution methods for 4-demethoxydaunorubicin or its precursors are known but are typically less convenient and efficient than the simple resolution using the compounds of this invention. Some methods rely on the separation of diastereomeric isomers formed upon reaction with the optically active glycoside daunosamine, for example, British Pat. No. 1,509,875 and U.S. Pat. No. 4,046,878, but these methods allow incorporation of only half of the expensive daunosamine in the preferred 4-demethoxydaunorubicin isomer.
Other methods form an optically active derivative at an intermediate step, with subsequent separation of isomers at some later step, but these methods are typically quite complex. See, e.g., S. Terashima et al. Asymmetric Synthesis of Optically Active Anthracyclinones. Tetrahedron Lett., 4937 (1978) (asymmetric "bromolactonization").
Other methods form an optically active precursor at an early step, with subsequent resolution of diastereomers required by later introduction of the asymmetric center at the 9-position--see (1) U.S. Pat. No. 4,077,988; (2) F. Arcamone et al. Synthesis and Antitumor Activity of 4-Demethoxydaunorubicin, 4-Demethoxy-7,9-diepidaunorubicin, and Their .beta. Anomers. Cancer Treat. Rep., 60, 829 (1976)--but such methods present the possibility of later racemization at the 7-position.